B-Raf kinase, a central component of the MAPK signaling pathway, was implicated in many types of malignant cancers including melanomas and thyroid cancers. Accumulating preclinical and clinical studies have suggested an unique opportunity for therapeutic interference by blocking the kinase activity of B-Raf. In this proposal, a set of pyridinopyrimidine analogs were designed as potential B-Raf inhibitors to treat cancers. The design was based on the understanding and insights derived from the analysis of the signature binding motif of this scaffold to protein kinases. The proprietary pyridinopyrimidine scaffold used in the design has demonstrated favorable kinase selectivity profiles, pharmacokinetic and drug properties. The proposed analogs will be synthesized and tested against B-Raf kinases and cancer cell lines. Desirable compounds will be moved quickly to preclinical and clinical studies.